Advanced tissue engineering strategies for generating replacement tracheal tissues

恶性肿瘤、声门下狭窄和气管外伤性损伤需要手术切除。当涉及短节段时，初级再吻合可获得良好的效果。然而，长期病变目前没有可接受的解决方案。有些病人需要永久性气管切开术或只接受姑息性治疗。气道移植的最新进展为这些问题的潜在解决方案提供了新的乐观，尽管仍有许多工作要做。使用构建底物的组织工程溶液提供了一种更简单的方法，大大降低了免疫原性风险。迄今为止，大量的工作已经取得了令人兴奋的进展，但主要集中在软骨细胞再生和结构完整性方面。气道上皮具有多种功能：屏障功能、粘液分泌功能和对吸入病原体的黏毛清除功能，但目前对其的关注较少。后一种作用需要组成整个气道树的数百万上皮细胞的纤毛同步、排列跳动。控制最佳上皮成熟和组织的因素几乎没有被探索，更不用说定义了。目前的合作建议将把工程师和临床医生团队聚集在一起，以加强我们对可以控制上皮组织和组织功能的物理因素的理解。具体来说，我们将把发育中的上皮暴露在受控的物理力量下，并检查由此产生的对二维和三维上皮组织的影响。我们假设物理力会影响上皮细胞的生长、组织和功能成熟，这些上皮细胞是由工程基膜上的局部祖细胞生长而来的，并且在组织发育过程中工程特定的物理力将为提高质量和临床应用提供一种新的策略

Malignancy, subglottic stenosis, and traumatic injury to the trachea require surgical resection. When short segments are involved, primary re-anastomosis affords excellent results. Longer lesions, however, have no currently acceptable solution. Some patients need permanent tracheostomies or receive only palliative treatment. Recent progress in airway transplantation has provided renewed optimism for potential solutions to these problems, however much remains to be done. Tissue engineered solutions, using constructed substrates, offer the best hope for a far simpler approach with much reduced risk of immunogenicity. Substantial work to date has provided exciting progress but has largely focused on chondrocyte regeneration and structural integrity. The epithelial layer of the airway has several functions: a barrier function, secretion of mucous, and mucociliary clearance of inhaled pathogens yet it has received much less attention. This latter role requires the synchronized, aligned beating of the cilia of the many millions of epithelial cells comprising the entire airway tree. The factors controlling optimal epithelial maturation and organization have barely been explored let alone defined. The present collaborative proposal will bring together a team of engineers and clinicians to enhance our understanding of physical factors that can be engineered to control epithelial organization and tissue functionality. Specifically, we will expose developing epithelium to controlled physical forces and examine the resulting effects on epithelial organization in two and three-dimensional epithelial layers. We hypothesize that physical forces will influence the growth, organization and functional maturation of the epithelial cells, grown from local progenitors on engineered basement membrane, and that engineering specific physical forces during tissue development will provide a novel strategy for improving the quality and clinical utility of